1. Technical Field
The present invention relates to compositions for and a method of treatment of neuronal degeneration due to stroke, brain, retina or spinal cord injuries and other brain or retinal disorders by glucocorticoids or glutamine synthetase.
2. Background Art
Neuronal degeneration as a result of stroke, brain, retina or spinal cord injuries, ischemia and reperfusion and other brain or retinal disorders is an enormous medical and public health problem by virtue of both its high incidence and the frequency of long-term sequelae. The pathophysiology of neuronal degeneration has been shown to be directly related to the neurotransmitter glutamate. Upon injury or upon ischemic insult, the damaged neurons release massive amounts of the neurotransmitter glutamate, which is excitotoxic to the surrounding neurons Choi, 1988; Rothman and Olney, 1986; Choi and Rothman, 1990; David et al., 1988; Drejer et al., 1985!. See also U.S. Pat. No. 5,135,956 issued Aug. 4, 1992 particularly columns 1-8 and U.S. Pat. No. 5,395,822 issued Mar. 7, 1995 columns 1-3 for a review, incorporated herein in their entirety by reference.
Under normal conditions, accumulation of glutamate in the extracellular space is prevented by the operation of a recycling mechanism which serves to maintain neuronal glutamate levels despite continual loss through transmitter release Van der Berg and Garfinkel, 1971; Kennedy et al., 1974!. Glutamate, released by glutaminergic neurons, is taken up into glial cells where it is converted into glutamine by the enzyme glutamine synthetase L-glutamate: ammonia ligase (ADP-forming; EC 6.3.1.2)! (GS); glutamine reenters the neurons and is hydrolyzed by glutaminase to form glutamate, thus replenishing the neurotransmitter pool. This biochemical pathway may also serve as an endogenous neuroprotective mechanism, which functions by removing the synaptically released glutamate from the extracellular space and converting it to the nontoxic amino acid glutamine before toxicity occurs. This neuroprotective mechanism fails, however, to prevent glutamate neurotoxicity after insult.
Massive release of glutamate to the extracellular fluid stimulates a cascade of events that amplifies the initial trauma and causes the damage to spread to the neighboring cells Mattson, 1990a; Olney, 1989; Olney, 1994a!. This biochemical cascade of induction and progression may continue for hours or days and causes delayed neuronal death. The object of medical therapy is to break or eliminate this cascade process and thus prevent spread of the secondary damage.
Involvement of glutamate in neuronal degeneration is supported by three major lines of evidence.
I. Neuronal insult leads to accumulation of relatively high levels of glutamate in the extracellular fluid Drejer et al., 1985; Waniewski and Martin, 1986!. PA1 II. Administration of glutamate (systematically or in vitro) leads to neuronal cell death Mattson, 1990b; Michaels and Rothman, 1990!. PA1 III. Glutamate receptor antagonists can protect from neuronal degeneration Clifford et al., 1998; Mosinger et al., 1991; Olney, 1994b; Olney et al., 1991!.
The mechanism responsible for the glutamate mediated cellular damage and death is not fully understood. However, accumulating evidence supports the hypothesis that glutamate neurotoxicity is mediated through NMDA and non-NMDA-type glutamate excitatory receptors Simon et al., 1984; Tecoma et al., 1989; Mosinger et al., 1991; Olney et al., 1991! and entails sustained depolarization of postsynaptic dendrosomal membranes, increased membrane permeability and impaired ion homeostasis Olney, 1989; Moudy et al., 1994; Waniewski and Martin, 1984; Olney et al., 1986; Dubinsky and Rothman, 1991; Choi, 1995! and lead to either an apoptotic or a necrotic type of death Bonfoco et al., 1995; Ankarcrona et al., 1995!. Although definitive evidence implicating specific ions has been lacking, several studies proposed that excessive calcium influx into the postsynaptic neuron may be responsible for activating signaling pathways and possibly endonucleases which cause neuronal cell death Olney, 1994; Michaels and Rothman, 1990; Dubinsky and Rothman, 1991!.
Several studies have shown the involvement of glutamate in the pathophysiology of Huntington's disease (HD) Coyle and Schwarcz, 1976!, Alzheimer's disease (AD)Maragos et al, 1987!, epilepsy Nadler et al, 1978!, lathyrism Spencer et al, 1986!, amyotrophic lateral sclerosis (ALS) and Parkinsonian dementia of Guam Calne et al, 1986! as well as in the neuropathology associated with stroke, ischemia and reperfusion Rothman, 1984; Dykens et al, 1987!.
U.S. Pat. No. 5,135,956 discloses treating neuronal degeneration by treating with a long-chain fatty alcohol which has cytoprotective effect. U.S. Pat. No. 5,395,822 discloses treating neuronal degeneration with a salt of pyruvic acid. Further U.S. Pat. Nos. 5,444,095, 5,428,069, 5,162,375 and 5,013,558 disclose other compounds for the treatment of neuronal degeneration. However, none of these approaches utilizes glutamine synthetase to block the cascade resulting in neurotoxicity at the initiation step by directly neutralizing the activity of its trigger: glutamate.